Amyloid formation plays a central role in over 20 human diseases, for example, Alzheimer's disease, type II diabetes, and the systemic amyloidoses (for review, see Pepys, M B Annu. Rev. Med. 2006. 57:8.1-8.19). It occurs when a normally soluble protein is extracellularly deposited as fibrils with characteristic properties (long, unbranched fibrils producing a cross-beta X-ray diffraction pattern and binding the dyes Congo red and Thioflavin T). The 20-odd proteins known to reassemble in this surprisingly similar manner share no apparent sequence, structural, or functional similarity in their native states.
β-2 microglobulin (also referred to herein as B2M or β-2M) is the ˜12 kDa subunit of the cell-surface MHC Class I complex and is normally found at circulating concentrations of 1-2 mg/L. When a patient's kidneys fail, such as for patients undergoing kidney dialysis, the kidneys are unable to effectively filter and catabolize the β-2 microglobulin and its circulating concentrations can soar to as high as 50-70 mg/L (Pepys, M B Annu. Rev. Med. 2006. 57:8.1-8.19).
Over 300,000 people in the United States and over 1 million worldwide are on kidney or peritoneal dialysis. (United States Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., 2005).
After about 5 years on dialysis, β-2 microglobulin may deposit as amyloid fibrils, primarily in the joints of patients as amyloid in a painful condition known as dialysis-related amyloidosis (herein, DRA) (Yamamoto, S. and F. Gejyo (2005). “Historical background and clinical treatment of dialysis-related amyloidosis.” Biochim Biophys Acta 1753(1): 4-10), which is a form of systemic amyloidosis. DRA often presents as carpal tunnel syndrome with or without other destructive arthropathies and can be detected by MRI. One-third of the patients on hemodialysis will develop dialysis-related amyloidosis within 4 years; after 7 years, more than 90% will be affected, and by 15 years on hemodialysis, all patients will have DRA (Jadoul, M. (1998). “Dialysis-related amyloidosis: importance of biocompatibility and age.” Nephrol Dial Transplant 13 Supp 7: 61-4). Thus, DRA eventually affects all long-term kidney dialysis patients. If left untreated, the systemic amyloidosis can be deadly. Amyloid deposits may develop in the heart and kill the patient.
High-flux dialysis membranes used during dialysis have improved β-2 microglobulin filtration, but have not eliminated DRA (Ayli, M., D. Ayli, et al. (2005). “The effect of high-flux hemodialysis on dialysis-associated amyloidosis.” Ren Fail 27(1): 31-4). Additionally, B2M adsorption columns have been used in conjunction with high-flux dialysis membranes with some improvement in DRA patients (Abe, T., K. Uchita, et al. (2003). “Effect of beta(2)-microglobulin adsorption column on dialysis-related amyloidosis.” Kidney Int 64(4): 1522-8; Winchester, J. F., J. A. Salsberg, et al. (2003). “Beta-2 microglobulin in ESRD: an in-depth review.” Adv Ren Replace Ther 10(4): 279-309). However, these columns are not highly specific for B2M and can have deleterious effects (Tsuruoka, S., M. Wakaumi, et al. (2004). “Beta2-microglobulin adsorption column reduces digoxin trough level during hemodialysis: three case reports.” Ther Drug Monit 26(4): 450-2). Currently the only effective means of combating the amyloidosis is kidney transplantation. See “Beta-2 microglobulin in ESRD: an in-depth review” Winchester et al., Adv in Renal Replacement Ther (2003) Vol. 10(4): 279-309; “Historical background and clinical treatment of dialysis-related amyloidosis” Yamamoto et al., Biochim Biophys Acta (2005) November 10;1753(1):4- 10.
Disrupting the β-2 microglobulin fibrils has potential therapeutic application in treating DRA. A compound that could disrupt these preformed aggregates could potentially remedy the amyloidosis and delay or eliminate the need for transplantation. Therefore, there is a need for compounds that can disrupt β-2 microglobulin fibrils.